This invention relates to certain novel analogs of the naturally occurring prostaglandins. In particular, it relates to novel 11-desoxy-15-substituted-.omega.-pentanorprostaglandins and various novel intermediates useful in their preparation.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, the prostaglandins of the E and A series are potent vasodilators (Bergstrom, et al., Acta Physiol. Scand. 64:332-33, 1965 and Bergstrom, et al., Life Sci. 6:449-445, 1967) and lower systemic arterial blood pressure (vasodepression) on intravenous administration (Weeks and King, Federation Proc. 23:327, 1964; Bergstrom, et al., 1965, op. cit.; Carlson, et al., Acta Med. Scand. 183:423-430, 1968; and Carlson, et al., Acta Physiol. Scand. 75:161-169, 1969). Another well known physiological action for PGE.sub.1 and PGE.sub.2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).
Still another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE.sub.2 is known to possess the ability to induce labor (Karim, et al., J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 (1971) and to be useful for control of fertility (Karim, Contraception, 3, 173 (1971)). Patents have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals (Belgian Patent No. 754,158 and West German Patent No. 2,034,641), and on PGE.sub.1, F.sub.2 and F.sub.3 for control of the reproductive cycle (South African Patent No. 69/6089). It has been shown that luteolysis can take place as a result of administration of PGF.sub.2.alpha. [Labhsetwar, Nature, 230, 528 (1971)] and hence prostaglandins have utility for fertility control by a process in which smooth muscle stimulation is not necessary.
Still other known physiological activities for PGE.sub.1 are in the inhibition of gastric acid secretion (Shaw and Ramwell, In: Worchester Symp. on Prostaglandins, New York, Wiley, 1968, p. 55-64) and also of platelet aggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967).
It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. Evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by .beta.-oxidation of the carboxylic acid side-chain and by oxidation of the 15.alpha.-hydroxy group (Anggard, et al., Acta. Physiol. Scand. 81, 396 (1971) and reference cited therein). It has been shown that placing a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action possibly by preventing the oxidation of the C15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins, 1, 319 (1972).
11-desoxy-15-substituted prostaglandins of the E.sub.1 and E.sub.2 series are disclosed in Netherlands Patent 730 1094, including the 15-alkyl and 15-benzyl compounds.
It was, of course, considered desirable to create analogs of the prostaglandins which would have physiological activities equivalent to the natural compounds, but in which the selectivity of action and the duration of the activity would be increased. Increased selectivity of action would be expected to alleviate the severe side effects, particularly gastrointestinal side effects frequently observed following systemic administration of the natural prostaglandins (Lancet, 536, 1971).